ABSTRACT Robust CD4 T cell responses are likely to be critical for any protective HIV vaccine through their multifaceted support of immune effectors, but as the primary targets of HIV infection their contribution to host immunity has been relatively understudied. We have recently demonstrated CD4 T cell immune responses are capable of driving viral adaptation, but the mechanism of this activity and its relevance to overall disease pathogenesis is unknown. A CD4 T cell subset, the T follicular helper cell (Tfh), has become a focus of investigation for its role in B cell differentiation and maturation as well as its facilitation of pathogen-specific high-affinity neutralizing antibody responses. CD4 T cells also have cytotoxic potential, a phenotype we have shown is compromised by single amino acid changes in viral epitopes suggesting a role in viral escape. We hypothesize viral adaptation compromises the immunologic functions of CD4 T cells resulting in a survival benefit for HIV and impacting the clinical course of disease. We will test this hypothesis in three separate aims: Specific Aim 1: Through TCR sequencing, determine the effects of viral adaptation on CD4 T cells ability to bind antigen and appropriately activate in response to stimulation. Specific Aim 2: Define the impact of viral adaptation on CD4 T cell effector functions as expressed by cytotoxic capacity and expansion of the Tfh phenotype. Specific Aim 3: Determine whether persons infected with highly adapted virus have accelerated HIV-1 clinical disease progression. The proposed aims will reveal the mechanism underlying viral adaptation to CD4 T cell immune pressure and the impact on disease. To support these efforts, I have developed a collaborative program that will provide access to primary tissues from deceased-donors, offering a unique opportunity to corroborate findings observed in peripheral blood samples with those from tissue-derived lymphocytes. The mentorship team combines a strong record of trainee development and expertise in the areas most relevant to the planned experiments. I also present a curriculum designed to enhance my immunologic knowledge, technical repertoire, statistical knowledge and professional development. The proposal will facilitate development of the skills necessary to identify clinically relevant research questions and advance the understanding of immunity to HIV and other chronic viral infections.